Elimination of B-RAF in Oncogenic C-RAF-expressing Alveolar Epithelial Type II Cells Reduces MAPK Signal Intensity and Lung Tumor Growth
| Autor: | Axel Ullrich, Ulf R. Rapp, Katharina Weidmann, Rajkumar Savai, Verena Pfeiffer, Nefertiti El-Nikhely, Emanuele Zanucco, Rudolf Götz, Werner Seeger |
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| Rok vydání: | 2014 |
| Předmět: |
Adenoma
Proto-Oncogene Proteins B-raf MAPK/ERK pathway Cell signaling Lung Neoplasms MAP Kinase Signaling System Mice Transgenic Respiratory Mucosa MAPK cascade Biology medicine.disease_cause Biochemistry Mice medicine Animals Humans c-Raf Molecular Biology Kinase Cell growth Epithelial Cells Cell Biology Cell biology Proto-Oncogene Proteins c-raf Pulmonary Alveoli Cell Transformation Neoplastic Mutation Signal transduction Carcinogenesis Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 289:26804-26816 |
| ISSN: | 0021-9258 |
| Popis: | Tumors are often greatly dependent on signaling cascades promoting cell growth or survival and may become hypersensitive to inactivation of key components within these signaling pathways. Ras and RAF mutations found in human cancer confer constitutive activity to these signaling molecules thereby converting them into an oncogenic state. RAF dimerization is required for normal Ras-dependent RAF activation and is required for the oncogenic potential of mutant RAFs. Here we describe a new mouse model for lung tumor development to investigate the role of B-RAF in oncogenic C-RAF-mediated adenoma initiation and growth. Conditional elimination of B-RAF in C-RAF BxB-expressing embryonic alveolar epithelial type II cells did not block adenoma formation. However, loss of B-RAF led to significantly reduced tumor growth. The diminished tumor growth upon B-RAF inactivation was due to reduced cell proliferation in absence of senescence and increased apoptosis. Furthermore, B-RAF elimination inhibited C-RAF BxB-mediated activation of the mitogenic cascade. In line with these data, mutation of Ser-621 in C-RAF BxB abrogated in vitro the dimerization with B-RAF and blocked the ability to activate the MAPK cascade. Taken together these data indicate that B-RAF is an important factor in oncogenic C-RAF-mediated tumorigenesis. |
| Databáze: | OpenAIRE |
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